Magnetic resonance (MR) is widely used for obtaining spatial images of human subjects for clinical diagnosis. A review of this technology and clinical applications is provided by D. P. Swanson et al., in Pharmaceuticals in Medical Imaging, 1990, Macmillan Publishing Company, pages 645-681.
MR images are derived as a composite of the effects of a number of parameters which are analyzed and combined by computer. Choice of the appropriate instrument parameters, such as radio frequency (Rf), pulsing and timing can be utilized to enhance or attenuate the signals of any of the image-producing parameters thereby improving image quality and provide better anatomical and functional information. In many cases, MR imaging has proven to be a valuable diagnostic tool, inasmuch as normal and diseased tissue, by virtue of their possessing different parameter values, can be differentiated in the image.
In MR imaging, the in vivo image of an organ or tissue is obtained by placing the body of a subject in a strong external magnetic field, pulsing with radio frequency energy, and observing the effect of the pulses on the magnetic properties of the protons contained in and surrounding the organ or tissue. A number of parameters can be measured. The proton relaxation times, T.sub.1 and T.sub.2, are of primary importance. T.sub.1, also called the spin-lattice or longitudinal relaxation time, and T.sub.2, also called the spin-spin or transverse relaxation time, are functions of the chemical and physical environment of the organ or tissue water and are measured using Rf pulsing techniques. This information is analyzed as a function of spatial location by computer which transforms the information to generate an image.
Often the image produced lacks appropriate contrast, e.g., between normal and diseased tissue, reducing diagnostic effectiveness. To overcome this drawback, contrast agents have been used. Contrast agents are substances which exert an effect on the MR parameters of various chemical species proximal to them. Theoretically, a contrast agent, if taken up preferentially by a certain portion of an organ or a certain type of tissue, e.g., diseased tissue, can provide contrast enhancement in the resultant images.
Inasmuch as MR images are strongly affected by variations in the T.sub.1 and T.sub.2 parameters, it is desirable to have a contrast agent which affects either or both parameters. Research has focused predominantly on two classes of magnetically active materials, i.e., paramagnetic materials, which act primarily to decrease T.sub.1, and superparamagnetic materials, which act primarily to decrease T.sub.2.
Paramagnetism occurs in materials that contain unpaired electrons. Paramagnetic materials are characterized by a weak magnetic susceptibility (response to an applied magnetic field). Paramagnetic materials become weakly magnetic in the presence of a magnetic field and rapidly lose such activity, i.e., demagnetize, once the external field has been removed. It has long been recognized that the addition of paramagnetic solutes to water causes a decrease in the T.sub.1 parameter.
Paramagnetic materials, for example, Gd containing materials, have been used as MR contrast agents primarily because of their effect on T.sub.1. Gd has the largest number of unpaired electron (seven) in its 4f orbitals and exhibits the greatest longitudinal relaxivity of any element.
A major concern with the use of contrast agents for MR imaging is that many paramagnetic materials exert toxic effects on biological systems making them inappropriate for in vivo use. For example, the free solubilized form of Gd salts are quite toxic. To make the gadolinium ion more suitable for in vivo use, researchers have chelated it with diethylenetriaminepentaacetic acid (DTPA). A formulation of this material that has undergone extensive clinical testing consists of Gd-DTPA neutralized with two equivalents of N-methyl-D-glucamine (meglumine). This agent has been successful in enhancing human brain and renal tumors.
Despite its satisfactory relaxivity and safety, this formulation has several disadvantages. For example, due to its low molecular weight, Gd-DTPA dimeglumine is cleared very rapidly from the blood stream and tissue lesions (tumors). This limits the imaging window, the number of optimal images that can be taken after each injection, and increases the agents required dose and relative toxicity. In addition, the biodistribution of Gd-DTPA is suboptimal for imaging body tumors and infections due to its small molecular size.
Several approaches have been taken in attempts to overcome these disadvantages. For example, Gd and Gd-chelates have been chemically conjugated to macromolecular proteins such as albumin, polylysines and immunoglobulins. Drawbacks of conjugating DTPA to protein carriers for use in MR image enhancement include inappropriate biodistribution and toxicity. In addition, proteins provide a defined platform not subject to wide synthetic variation. Additionally, thermal sterilization of protein conjugates tends to be problematic, especially in the case of albumin conjugates.
To overcome these drawbacks, PCT/US93/09766 contacts a chelating agent with poly(alkylene oxide) to form a metallizable polymer which, when associated with paramagnetic metal ions, provide polymeric chelates with improved utility as contrast agents for MR imaging. For example, such polymeric chelates contain relatively large amounts of metal, are potentially more stable in vivo, and are less immunoreactive than protein-chelate-metal complexes.
However, incorporation of the poly(alkylene oxide) moiety into the backbone of the polymer contributes to increased viscosity of the polymeric composition, thereby limiting formulation concentration and raising injection volume in order to maintain acceptable formulation viscosity.
Thus, it is readily apparent that it would be highly desirable to provide other polymeric MR contrast agents which also contain relatively large amounts of metal per molecule, i.e., are of high substitution ratios; are of a molecular weight enabling them to be circulated within the blood pool for extended periods of time; exhibit improved biodistribution for imaging blood vessels, body tumors and other tissues; yet yield low viscosity contrast compositions that maximize injectable concentration and minimize injectable volume.